Polyester Modification of the Mammalian TRPM8 Channel Protein: Implications for Structure and Function
Chike Cao,
Yevgen Yudin,
Yann Bikard,
Wei Chen,
Tong Liu,
Hong Li,
Dieter Jendrossek,
Alejandro Cohen,
Evgeny Pavlov,
Tibor Rohacs,
Eleonora Zakharian
Affiliations
Chike Cao
Department of Pharmacology and Physiology, New Jersey Medical School, UMDNJ, 185 South Orange Avenue, MSB H626, Newark, NJ 07103, USA
Yevgen Yudin
Department of Pharmacology and Physiology, New Jersey Medical School, UMDNJ, 185 South Orange Avenue, MSB H626, Newark, NJ 07103, USA
Yann Bikard
Department of Pharmacology and Physiology, New Jersey Medical School, UMDNJ, 185 South Orange Avenue, MSB H626, Newark, NJ 07103, USA
Wei Chen
Center for Advanced Proteomics Research, New Jersey Medical School Cancer Center, UMDNJ, Building F1105, 205 South Orange Avenue, Newark, NJ 07103, USA
Tong Liu
Center for Advanced Proteomics Research, New Jersey Medical School Cancer Center, UMDNJ, Building F1105, 205 South Orange Avenue, Newark, NJ 07103, USA
Hong Li
Center for Advanced Proteomics Research, New Jersey Medical School Cancer Center, UMDNJ, Building F1105, 205 South Orange Avenue, Newark, NJ 07103, USA
Dieter Jendrossek
Universität Stuttgart Zentrum für Bioverfahrenstechnik, Institut für Mikrobiologie, Allmandring 31, 70569 Stuttgart, Germany
Alejandro Cohen
Proteomics Core Facility, Clinical Research Centre, Dalhousie University, Room C-304, 5849 University Avenue, P.O. Box 15000, Halifax NS B3H 4R2, Canada
Evgeny Pavlov
Department of Physiology and Biophysics Faculty of Medicine, Dalhousie University, Sir Charles Tupper Medical Building, Room 5G, 5850 College Street, Halifax NS B3H 4R2, Canada
Tibor Rohacs
Department of Pharmacology and Physiology, New Jersey Medical School, UMDNJ, 185 South Orange Avenue, MSB H626, Newark, NJ 07103, USA
Eleonora Zakharian
Department of Pharmacology and Physiology, New Jersey Medical School, UMDNJ, 185 South Orange Avenue, MSB H626, Newark, NJ 07103, USA
The TRPM8 ion channel is expressed in sensory neurons and is responsible for sensing environmental cues, such as cold temperatures and chemical compounds, including menthol and icilin. The channel functional activity is regulated by various physical and chemical factors and is likely to be preconditioned by its molecular composition. Our studies indicate that the TRPM8 channel forms a structural-functional complex with the polyester poly-(R)-3-hydroxybutyrate (PHB). We identified by mass spectrometry a number of PHB-modified peptides in the N terminus of the TRPM8 protein and in its extracellular S3-S4 linker. Removal of PHB by enzymatic hydrolysis and site-directed mutagenesis of both the serine residues that serve as covalent anchors for PHB and adjacent hydrophobic residues that interact with the methyl groups of the polymer resulted in significant inhibition of TRPM8 channel activity. We conclude that the TRPM8 channel undergoes posttranslational modification by PHB and that this modification is required for its normal function.
